Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

Surgery after sonidegib treatment achieves complete response in locally advanced basal cell carcinoma of the face.

Basal cell carcinoma accounts for 75% of skin cancers worldwide and is the most common malignancy in Caucasians. Since chronic ultraviolet exposure is the major risk factor for its development, sun-exposed areas such as the face are frequently affected. The gold-standard treatment is surgical excision. Radiotherapy may be considered in selected cases such as unresectable primary tumors. In some patients, when the risk of a significant functional/cosmetic deficit advises against both surgery and radiotherapy, target therapy (hedgehog pathway inhibitors) can be administered alone or in a neoadjuvant setting, to reduce the tumor size and make it eligible for surgery. Vismodegib as a neoadjuvant treatment before surgery has been investigated in a single, multicentre, open-label, phase II trial (VISMONEO); however, sonidegib has not yet been evaluated in this setting. We report the cases of two patients with locally advanced basal cell carcinoma of the face who achieved complete remission with sonidegib followed by a more limited surgical excision than would have been needed without target therapy.

Burden of disease during quiescent periods in patients with pemphigus.

BACKGROUND: Studies conducted using different tools have invariably observed that physical and mental components of health status are seriously compromised in patients with pemphigus. An improvement in quality of life (QoL) has been commonly observed over the treatment period. OBJECTIVES: The aim of the study is to verify whether the patients' wellbeing is affected by pemphigus also in absence of cutaneous and mucosal lesions. MATERIALS AND METHODS: The clinical records of 203 patients were analysed. A total of 47 patients were without bullae/erosions and reported a score = 0 for both the Patient Global Assessment and the Ikeda index. In order to assess the QoL we used the Skindex-17 and the 12-item General Health Questionnaire (GHQ-12). RESULTS: Patients without bullae/erosions had a better QoL when compared with patients with active lesions. This difference, with a reduction of approximately 30% of the Skindex-17 scores in the patients without lesions, was statistically significant, for both the symptoms and the psychosocial scales. The proportion of patients at risk of anxiety/depression (GHQ-positive cases) was 44% lower in patients without lesions compared with patients with lesions. In a multiple linear regression model the presence of bullae/erosions negatively influences QoL with an average increase of Skindex-17 symptoms and psychosocial scale scores of 11·7 and 10·6 points, respectively. Female patients had a statistically significantly worse QoL than males on the symptoms but not on the psychosocial Skindex-17 scales. CONCLUSIONS: While patients without lesions reported a better QoL than patients with bullae/erosions, their Skindex-17 scores remained elevated. Dermatologists should be aware that a clearing of the skin manifestations does not mean 'perfect health' for the patient.

Acute generalized exanthematous pustulosis during antituberculosis therapy.

Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction most often induced by drugs and by acute infections. Its clinical hallmark is the sudden onset of multiple, disseminated, non-follicular, sterile pustules on an erythematous background usually arising in intertriginous folds, associated with fever, massive neutrophilia and sometimes eosinophilia. Antitubercular therapy is described as an uncommon cause of AGEP. We report the onset of disseminated non-follicular sterile pustules on an erythematous background in a 68-year-old man receiving a combination of isoniazid, pyrazinamide and rifampicin that may have been the etiologic agents. A thorough history, including a medication history, with clinicopathologic correlation is crucial in patients presenting with acute diffuse pustular lesions.

Quality of life in patients with pemphigus receiving adjuvant therapy.

BACKGROUND: Pemphigus has a strong effect on patients' quality of life (QOL). AIM: To analyze QOL and psychological well-being within patient groups, subdivided according to their different adjuvant treatments. METHODS: All adult patients with pemphigus enrolled in the study were assessed using the Short Form (SF)-36, the Skindex-29, and the General Health Questionnaire (GHQ)-12 for health status, effect of dermatology-specific aspects, and the presence of psychological comorbidity, respectively. The study population was subdivided into the following treatment groups: (i) those who were untreated or were treated only with corticosteroids (CS) at a dose of ≤ 5 mg/day (no adjuvant treatment, NAT); and patients receiving or not receiving CS ≤ 5 mg/day who also received either (ii) azathioprine (AZ), (iii) cyclophosphamide (CY), (iv) mycophenolate mofetil (MM) or (v) rituximab (RTX). RESULTS: In total, 113 patients were recruited. There were no significant differences between the treatment subgroups in either the SF-36 or Skindex-29 results. However, for the GHQ, there were large differences in QOL scores between patients scoring > 4 points (GHQ+) and those scoring < 4 points (GHQ-), especially for the more 'physical' components of QOL. The overall observed proportion of GHQ+ patients was 33.6%. CONCLUSIONS: We found no significant differences in QOL impairment between the treatment subgroups; however, we observed a strong association between psychiatric morbidity and poorer QOL within each of the treatment groups. This should be of concern for dermatologists, as psychiatric morbidity is associated with poor treatment adherence and dissatisfaction with care.

Disease severity evaluation among dermatological out-patients: a comparison between the assessments of patients and physicians.

BACKGROUND: The assessment of a patient's disease severity is an essential component in the formulation of treatment strategies. OBJECTIVES: To compare disease severity assessment by patients and by physicians, and to describe the possible discrepancies between them. METHODS: For each patient, we obtained the Physician Global Assessment (PhGA) and the Patient Global Assessment (PtGA). Data were completed for 2.578 patients. Sixty-one physicians participated in the study. We calculated the agreement between PtGA and PhGA scores using the weighted kappa statistics; a multinomial logistic regression was performed to assess the risk of disagreement considering both patient and physician variables. RESULTS: Differences in the percentages of severity level, identified by patients and by physicians, were always statistically significant (P < 0.05). Overall, the weighted Cohen's kappa was in the range of 0.09-0.34, depending on the diseases. Gender differences between patients and physicians did not influence the agreement. In the multinomial model female patients (OR = 1.38; 95% CI, 1.07-1.77), patients with higher educational levels (OR = 2.71; 95% CI, 2.12-3.46), and patients with impaired quality of life (OR = 1.56; 95% CI 1.23-1.97) had a higher risk to be underestimated for their disease severity by physicians, independently by physician gender and experience. CONCLUSIONS: Combining the subjective report with the objective severity assessment of the lesions, dermatologists may reach a better determination of how severity of disease is perceived by their patients and how they feel about the effectiveness of treatment. PtGA and PhGA might be considered in routine clinical assessments and not only for research activities.

Assessment of the health status of 2,499 dermatological outpatients using the 12-item Medical Outcomes Study Short Form (SF-12) questionnaire.

BACKGROUND: In dermatological research and clinical practice it is important to evaluate the burden of the disease. OBJECTIVE: To assess whether the 12-item Short Form of the Medical Outcomes Study (SF-12) could yield a valid description of the health status of a large number of dermatological outpatients. METHODS: The SF-12 and the 12-item General Health Questionnaire (GHQ-12) were utilized. Questionnaires were self-completed by the outpatients in the waiting rooms. At the end of the visit the dermatologists recorded the diagnosis and the evaluation of the clinical severity. RESULTS: Data were complete for 2499 patients. We observed a reduction in the Physical Component Summary score (PCS-12) with increasing age, while the Mental Component Summary score (MCS-12) was stable. PCS-12 and MCS-12 scores were worse in women. Twenty-three per cent of patients were identified as GHQ-12 positive. GHQ-12-positive patients ('cases') had lower PCS-12 and MCS-12 scores compared with GHQ-12-negative patients (mean ± SD, PCS-12: 47·9 ± 10·8 vs. 52·2 ± 6·6; MCS-12: 35·2 ± 10·2 vs. 50·9 ± 78·3, respectively). High correlations between the MCS-12 score and the GHQ-12 were documented overall (-0·690, P < 0·001) and for single skin diseases. CONCLUSIONS: The impact of dermatological diseases is high for the mental components of health status; the mean scores for MCS-12 were low, and lower in patients identified as GHQ-12 'cases'. The picture of the general health status of patients with skin diseases given by the SF-12 allows meaningful comparisons both within dermatological conditions and with diseases in other specialties, as well as within categories of clinical severity and psychological well-being in single skin conditions.

Seropositivity for human papillomavirus and incidence of subsequent squamous cell and basal cell carcinomas of the skin in patients with a previous nonmelanoma skin cancer.

BACKGROUND: Infection with human papillomaviruses (HPVs) is a risk factor for several epithelial cancers, but its relationship with keratinocyte tumours has not yet been established. Objective In this prospective study we investigated the possible role of different HPVs in the incidence of a subsequent nonmelanoma skin cancer (NMSC). METHODS: One hundred and fifty-three patients with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) enrolled in a previous case-control study were re-contacted, and a follow-up visit was offered. Demographic and clinical data, date of first NMSC presentation, Fitzpatrick skin type and history of NMSC during the follow-up period were ascertained. Recurrences and new second cancers were considered together as 'outcomes' in time-to-event analyses and in Cox proportional hazard models. RESULTS: Clinical data were obtained in 107 patients. HPV seropositivity at baseline was strongly associated with the risk of developing a second SCC after 5 years for a number of beta and gamma HPV types. For example, HPV-24-seropositive patients with an SCC at baseline had a 4-fold increased risk of developing a subsequent SCC (hazard ratio 4·35, 95% confidence interval 1·2-15·6, P = 0·024). No association between serological status for any HPV type tested and an increased risk of BCC was found. CONCLUSIONS: We observed a consistent pattern of a positive association between seropositivity for beta and gamma HPV types and the risk of a subsequent SCC in patients with a previous SCC. Our data corroborate the results of previous case-control studies and may spur further prospective studies on the causal role of HPVs in NMSC.

Quality of life in patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is a rare, inherited group of disorders characterized by blistering of the skin following friction or mechanical trauma. EB has a clinical and socioeconomic impact on patients and their families. OBJECTIVES: To assess the quality of life (QoL) in patients with EB and to determine disease burden. METHODS: The study was an observational, cross-sectional postal survey. One hundred and eighty-five patients were invited to participate. Different sets of questionnaires [Short Form-36 (SF-36), Skindex-29, General Health Questionnaire-12 (GHQ-12), EuroQol 5 dimensions] were sent to patients according to age. The perceived severity of the disease was evaluated by patients or by the mothers of the younger children with EB, using the Patient Global Assessment five-point scale. Carers received the Family Strain Questionnaire. RESULTS: One hundred and twenty-five respondents were analysed. Patients with EB showed lower values in physical components of the SF-36, while the mental components were not significantly impaired. Among EB types, patients with junctional EB and severe generalized recessive dystrophic EB reported lower values and their GHQ-12 scores were significantly different from those of patients with EB simplex. There were no significant differences among EB types/subtypes for Skindex-29 values. Women had a worse QoL compared with men in all Skindex-29 and SF-36 scales (P < 0.05). GHQ-positive cases were more frequent among women (48%) compared with men (16%) (P = 0.003); GHQ-positive cases had a worse QoL compared with GHQ-negative patients. The patient QoL decreased and the family burden increased with increasing patient perceived disease severity and with increasing patient body surface involved. No differences were seen among EB types for the family burden. CONCLUSIONS: In patients with EB mental components of SF-36 scores are similar to the normal population. The perceived disease severity and skin area involved are relevant for QoL in all EB types/subtypes. EB imposes a heavy burden on the caregiver and the family. Psychological support and close monitoring of QoL may help patients with EB and their carers.

Extragenital lichen sclerosus and atrophicus treated with topical steroids and retinoids in a child with vitiligo.

Lichen sclerosus and atrophicus (LSA) most commonly affects the anogenital region. Extragenital involvement is rare, and women are reported to be affected 6 to 10 times more often than men. The aetiology of LSA is unclear, but genetic, physiological and environmental factors are thought to be involved. Several lines of evidence support the hypothesis of an autoimmune basis for LSA; an increased incidence of tissue-specific antibodies and an association with autoimmune disorders such as vitiligo, alopecia areata, thyroid disease and pernicious anaemia have been reported. We describe a paediatric patient with extragenital LSA associated with vitiligo who was successfully treated with topical steroids and retinoids.

Dermatofibrosarcoma protuberans: wide local excision vs. Mohs micrographic surgery.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon tumor of the skin with high rates of local recurrence. It is debated whether Mohs micrographic surgery (MMS) involves lower recurrence rates than wide local excision (WLE). Recent preliminary reports indicate more consistently favorable cure rates with MMS. We report comparative observational data on 41 patients who underwent MMS and 38 who underwent WLE. Their data were then pooled with those available in the medical literature to obtain more precise estimates of recurrence rates with MMS and WLE. METHODS: The records of 79 patients with DFSP who underwent WLE (n=38) or MMS (n=41) in 1990-2005 were reviewed retrospectively. The primary endpoint was tumor recurrence rate. The PubMed database was searched for DFSP case series treated with WLE or MMS, and the recurrence proportions reported for the two separate procedures were pooled. RESULTS: Five of the 38 WLE patients (follow-up=4.8 years) had recurrences (13.2%, 95% CI 4.4-28.1%) as opposed to none (95% CI 0-8.6%) of the 41 MMS patients (follow-up=5.4 years). Pooling of these data with those from the literature yielded 6/463 recurrences for MMS (1.3%, 95% CI 0.5-2.8%) and 288/1394 recurrences for WLE (20.7%, 95% CI 18.6-22.9%). The relative risk of recurrence for WLE vs. MMS patients was 15.9 (95% CI 7.2-35.5). CONCLUSIONS: Significantly lower recurrence rates were recorded in our patients subjected to MMS compared with those treated with WLE. The pooled data also indicated a clear advantage of MMS. There is inconclusive evidence for any advantage of MMS in non-primary cases, while MMS was most effective in treating head and neck tumors. These data may be useful to guide clinicians in the choice of the more appropriate surgical treatment for DFSP patients.

Association between cutaneous melanoma, Breslow thickness and vitamin D receptor BsmI polymorphism.

BACKGROUND: Literature data report an association between some vitamin D receptor (VDR) polymorphisms and different kinds of tumours, including malignant melanoma (MM). Only three VDR polymorphisms (FokI, TaqI and A-1012G) have been investigated in association with the presence of cutaneous MM or the development of metastases. OBJECTIVES: The present paper analyses for the first time the association between BsmI polymorphism and MM prevalence together with Breslow thickness. In addition, the FokI single nucleotide polymorphism was also determined. METHODS: One hundred and one patients with MM and 101 healthy donors matched for age and sex were enrolled. Molecular VDR typing was performed by means of restriction fragment length polymorphism analysis. RESULTS: All cases and controls were in Hardy-Weinberg equilibrium for BsmI, FokI and A-1012G. Significant associations were found between the BsmI bb genotype frequency and MM (P = 0.02) along with Breslow thickness (P = 0.001). This same behaviour was not observed for the FokI or A-1012G polymorphisms. Multivariate logistic regression analysis confirmed these significant results after correction for age, gender, skin type and MM localization. CONCLUSIONS: Although the biological meaning of the effects exerted by BsmI polymorphism is still under debate, the statistical association found in the present study suggests that further work should be done to verify this variant as a possible risk marker for MM and its aggressiveness, also considering that the real association may be due to other unknown genes linked to the BsmI b allele.